Fewer than 50% of elderly depressed patients achieve remission and functional recovery in response to first-line antidepressant pharmacotherapy. The majority of patients are left with significant residual symptoms, putting them at risk of chronic, relapsing illness, frailty, and suicide. Improved understanding of neurobiology of geriatric depression and mechanisms of treatment response may lead to the improved clinical management of this pervasive and disabling disorder. While the serotonin system has been the focus of pharmacotherapy in unipolar major depression, there is a compelling rationale for the study of other monoamine systems. Impairment of executive functions persists even after amelioration of depressive symptoms and that these symptoms are poorly responsive to serotonergic treatment alone. We hypothesized that the addition of methylphenidate (MPH) to the serotonergic drug, citalopram, may result in better clinical outcomes of the affective and cognitive symptoms of late life depression. These considerations provided the impetus for our pilot study to evaluate the treatment response of the combination of citalopram and methylphenidate (MPH) compared to citalopram and placebo. We observed enhanced antidepressant response and improvement in executive cognitive function tests to a combination of citalopram and methylphenidate (MPH). The improvement in executive function was greater in patients who were homozygous for the dopamine transporter genotype (DAT VNTR10/10). The current proposal will evaluate the role of adjunctive MPH treatment to determine the effects of pharmacologic increase of dopamine on the clinical and cognitive response to selective serotonin reuptake (SSRI) treatment. We will also explore the role of the candidate genes involved in the regulation of dopaminergic neurotransmission (i.e., COMT, DAT1, DRD4) and sertonergic neurotransmission (i.e., HTR2A) in the clinical and cognitive response to treatment with methylphenidate and citalopram. We will recruit 168 elderly non-demented subjects with major depression to participate in a double-blind randomized placebo- controlled trial. Participants will be randomly assigned to three groups: one group will receive combination of citalopram and MPH, the second group will receive MPH and placebo, and the third group will receive citalopram and placebo. All subjects will undergo comprehensive medical, neuropsychiatric and cognitive assessments, and genetic testing at baseline and over the 16 weeks of treatment. Our study will provide the unique information regarding the use of methylphenidate to improve cognitive and clinical outcomes, and will shed light on the underlying mechanism of treatment response in geriatric depression. Evaluating selected dopamine-related genes in late-life depression with respect to mood and cognitive symptoms, and treatment response may lead to the development of the targeted individualized treatments in geriatric depression. [unreadable] [unreadable] [unreadable] [unreadable]